Chronic rhinosinusitis effects an estimated 15% of the population of the United States, and the prevalence of this disease has been rising over the past decade. Annual direct medical costs are conservatively estimated at $2.4 billion; excluding the costs associated with the almost 200,000 sinus surgeries performed each year. Despite the high incidence of chronic rihnosinusitis and its major impact on the health care system, little is known regarding the etiology and pathogenesis of this disease. Epithelial hyperplasia and inflammation are consistent and striking features of chronic rhinosinusitis. Indeed, imaging of these mucosal changes by CT or MRI is used to support diagnosis. It is our central hypothesis that epithelial cell/mucosal dysfunction plays a central role in the pathogenesis of chronic rhinosinusitis. This dysfunction may also arise due to an inherent genetic defect(s), environmental influences, or, more likely, a combination of the two. This Program Grant presents an integrated, multidisciplinary approach to test this central hypothesis, through a series of projects which address differing aspects of our central hypothesis. Project 1 evaluates the potential genetic predisposition of some subjects to develop chronic rhinosinusitis. Specifically, a variey of approaches will be used to further test the hypothesis that patients with chronic rhinosinusitis have a higher rate of mutations in the cystic fibrosis transmembrane regulator than the healthy population. Project 2 focuses on the role of a specific environmental factor, respiratory viral infection, as a trigger factor in altering epithelial cell function in a manner that plays a role in the pathogenesis of chronic rhinosinusitis. Project 3 has demonstrated that patients with refractory chronic rhinosinusitis demonstrate mucosal hyporesponsiveness to stimuli such as histamine, despite the presence of profound inflammation. Efforts will focus on determining the mechanisms underlying this hyporesponsiveness and on evaluating if there is a familial predisposition for mucosal hyporesponsiveness. The three projects will interact by sharing protocols, expertise and patients, as well as through intellectual exchange. All three projects depend absolutely on the CORE for recruitment and characterization of patients and control populations, and for critical support services. These studies should determine important insights into the pathogenesis of chronic rhinosinusitis and may lead to the development of new approaches for the treatment of this major health problem.